PMID- 18474596
OWN - NLM
STAT- MEDLINE
DCOM- 20080819
LR  - 20211020
IS  - 0021-9258 (Print)
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Linking)
VI  - 283
IP  - 27
DP  - 2008 Jul 4
TI  - Unique small molecule entry inhibitors of hemorrhagic fever arenaviruses.
PG  - 18734-42
LID - 10.1074/jbc.M802089200 [doi]
AB  - Viral hemorrhagic fevers caused by the arenaviruses Lassa virus in Africa and 
      Machupo, Guanarito, Junin, and Sabia virus in South America are among the most 
      devastating emerging human diseases with fatality rates of 15-35% and a limited 
      antiviral therapeutic repertoire available. Here we used high throughput 
      screening of synthetic combinatorial small molecule libraries to identify 
      inhibitors of arenavirus infection using pseudotyped virion particles bearing the 
      glycoproteins (GPs) of highly pathogenic arenaviruses. Our screening efforts 
      resulted in the discovery of a series of novel small molecule inhibitors of viral 
      entry that are highly active against both Old World and New World hemorrhagic 
      arenaviruses. We observed potent inhibition of infection of human and primate 
      cells with live hemorrhagic arenaviruses (IC(50)=500-800 nm). Investigations of 
      the mechanism of action revealed that the candidate compounds efficiently block 
      pH-dependent fusion by the arenavirus GPs (IC(50) of 200-350 nm). Although our 
      lead compounds were potent against phylogenetically distant arenaviruses, they 
      did not show activity against other enveloped viruses with class I viral fusion 
      proteins, indicating specificity for arenavirus GP-mediated membrane fusion.
FAU - Lee, Andrew M
AU  - Lee AM
AD  - Department of Immunology and Microbial Science, The Scripps Research Institute, 
      La Jolla, California 92037, USA.
FAU - Rojek, Jillian M
AU  - Rojek JM
FAU - Spiropoulou, Christina F
AU  - Spiropoulou CF
FAU - Gundersen, Anette T
AU  - Gundersen AT
FAU - Jin, Wei
AU  - Jin W
FAU - Shaginian, Alex
AU  - Shaginian A
FAU - York, Joanne
AU  - York J
FAU - Nunberg, Jack H
AU  - Nunberg JH
FAU - Boger, Dale L
AU  - Boger DL
FAU - Oldstone, Michael B A
AU  - Oldstone MB
FAU - Kunz, Stefan
AU  - Kunz S
LA  - eng
GR  - R01 AI074818/AI/NIAID NIH HHS/United States
GR  - 1U54 AI065359/AI/NIAID NIH HHS/United States
GR  - AI55540/AI/NIAID NIH HHS/United States
GR  - CA78045/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20080512
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Antiviral Agents)
RN  - 0 (Viral Fusion Proteins)
SB  - IM
MH  - Animals
MH  - Antiviral Agents/*chemistry/*pharmacology/therapeutic use
MH  - Arenaviridae Infections/*drug therapy
MH  - *Arenavirus
MH  - Chlorocebus aethiops
MH  - Communicable Diseases, Emerging/*drug therapy
MH  - Drug Evaluation, Preclinical
MH  - HeLa Cells
MH  - Hemorrhagic Fevers, Viral/*drug therapy
MH  - Humans
MH  - Vero Cells
MH  - Viral Fusion Proteins/*antagonists & inhibitors
MH  - Virion/metabolism
PMC - PMC2441566
EDAT- 2008/05/14 09:00
MHDA- 2008/08/20 09:00
PMCR- 2009/07/04
CRDT- 2008/05/14 09:00
PHST- 2008/05/14 09:00 [pubmed]
PHST- 2008/08/20 09:00 [medline]
PHST- 2008/05/14 09:00 [entrez]
PHST- 2009/07/04 00:00 [pmc-release]
AID - S0021-9258(20)81474-4 [pii]
AID - 18734 [pii]
AID - 10.1074/jbc.M802089200 [doi]
PST - ppublish
SO  - J Biol Chem. 2008 Jul 4;283(27):18734-42. doi: 10.1074/jbc.M802089200. Epub 2008 
      May 12.